Traumatic brain injury (TBI), which involves damage to the brain from an external force, contributes to a substantial number of deaths and cases of permanent disability both in the Veteran population as well as in the general population each year. TBI is the most common neurological diagnosis in the U.S. and has been identified as a serious public health problem. While the consequences and mechanisms of primary injury to the head on the pathophysiological and neurochemical events that occur during the course of initial hours and days are being extensively investigated, little is known on the long term consequence of TBI on remote organs that are under hypothalamic control via the pituitary. In this merit review proposal, we have chosen to study the TBI effect on the skeletal system based on the following rationale. Recently, the discovery of bone regulation by neural signals represents an emerging area of study that is identifying novel regulatory axes between the nervous system and bone cells. In this regard, it is well known that the hypothalamic region of the brain controls the endocrine system via the pituitary. Notably, the hypothalamus secretes growth hormone releasing hormone (GHRH) which acts on the pituitary gland to regulate production of growth hormone (GH), an important hormone that regulates skeletal metabolism. It is estimated that 30-50% of TBI patients suffer from hypopituitarism. Besides, recent studies demonstrate an important role for central control of bone mass involving leptins and neuropeptides. Based on the important role for cells of the hypothalamic nuclei in the neuro (endo)crine regulation of bone remodeling, it is predictable that injury to the brain will have a severe impact on the regulatory molecules that control skeletal growth and maintenance. Based on the above rationale, we propose to test the following hypotheses in this study: 1) TBI, even in its milder form, exerts lon lasting negative effects on bone growth and maintenance and the ability of skeleton to repair the damaged tissue in response to injury. 2) The attenuating effects of TBI on bone formation (BF) are mediated in part via down regulation of the GH/insulin-like growth factor-I axis. 3) TBI exaggerates the negative effects of skeletal unloading on BF. To test these hypotheses, we will use a recently established mouse model of human repetitive mild TBI which utilizes the weight drop method to create a closed head injury. We have proposed to use the mild TBI model as approximately 85% of the 1.7 million cases of TBI reported annually in the United State represent mild cases. In our preliminary studies, we have validated the usefulness of the mild TBI mouse model for studies on bone. In order to determine if mild TBI exerts negative effects on the ability of the skeleton to regenerate injuries, we will induce a standard closed femoral fracture and evaluate repair using micro-CT, histology and gene expression end points. To evaluate the role of the GH/IGF-I axis, we will determine if changes in GH/IGF-I levels in the TBI mice are caused by reduced expression of GHRH in the hypothalamus by immunohistochemistry. To determine if reduced GH/IGF production contributes to impaired BF in mice, we will administer GH to TBI mice and evaluate if TBI-induced changes in BF and bone regeneration are rescued by GH replacement. We will utilize a GH deficient lit/lit mouse model to evaluate the role of GH in TBI-induced bone loss. We will also determine if TBI and skeletal unloading lead to greater BF deficits than either condition alone since TBI patients are bedridden for extended periods immediately post injury and since skeletal unloading induces resistance to IGF-I by inhibiting activation of the IGF-I signaling pathways. We will subject TBI and control mice to skeletal unloading using the tail suspension hind limb elevation model or to normal loading and evaluate skeletal parameters by micro-CT, histomorphometry or gene expression analyses. We believe that our successful confirmation of proposed hypotheses will lead to development of new therapeutic strategies to promote long-term health of TBI patients.